Familial aggregation and definite patterns of inheritance are seen in a variety of forms of arthritis that include some of the most prevalent causes of disability; yet only a beginning has been made in the identification of the specific genetic and biochemical abnormalities of metabolism and the detailed mechanisms by which they lead to the arthritis. Even in gouty arthritis where the general pathogenetic mechanisms are best understood, only a few of the many underlying genetic factors have been characterized and those only recently. In ochronotic arthritis where the primary genetic defect producing alcaptonuria has been defined, the detailed molecular mechanism by which the accumulation of homogentisic acid produces the ochronotic arthritis accompanying alcaptonuria remains to be elucidated. Likewise in chondrocalcinosis the primary metabolic defect causing an increased concentration of inorganic pyrophosphate in synovial fluid is unknown and the precise sequence of events leading to formation of calcium pyrophosphate crystals causing the joint symptoms is but poorly understood. Specific objectives of the proposed research will be to identify additional genetic and biochemical factors underlying various types of heritable arthritis, to determine the mechanism by which the biochemical lesion leads to the pathological process and to devise more rational forms of therapeutic intervention by nutritional or pharmacological agents to prevent the pathology. Studies will first be made in vitro at the molecular, biochemical and cellular levels using cultured chondrocytes and human fibroblasts. Whenever feasible, investigations that appear promising in vitro will then be extended to clinical studies of patients with the various diseases and a study will be undertaken to find evidence of the operation in vivo of the same pathological processes and to evaluate the effectiveness of various avenues of therapeutic intervention in preventing development of the disease.